Hematopoiesis is a complex process for producing multiple and distinct lineages of blood-borne cells throughout the life span of an organism. Hematopoietic stem cells (“HSCs”) represent a subset of undifferentiated cells that resides predominantly in the bone marrow of adult mammals. HSCs, as a population, are capable of self-renewal by maintaining a sufficient number of HSCs within an organism's bone marrow as a reservoir of uncommitted cells that can be further differentiated into various types of new blood cells. Such newly generated blood cells emerge from the bone marrow and enter the circulatory system in order to continuously replace mature/aging circulating blood cell types. The ability of HSCs, as a population, to differentiate and to give rise to cells of multi-lineages is critical for the preservation of an organism.
In order for the maintenance of steady-state hematopoiesis, a balance must be achieved between the rate of self-generation (i.e., for maintaining a steady supply of HSCs) and the rate of differentiation (i.e., for replenishing senescent cells). Hematopoiesis occurs as a developmental continuum in that a given population of HSCs is representative of a heterogeneous mixture of cells, mainly composed of long-term HSCs (“LT-HSCs”) and short-term HSCs (“ST-HSCs”). LT-HSCs are stem cells that have the capacity for self-renewal throughout the life span of an organism. However, ST-HSCs exhibit transient self-renewal properties for a limited period of time (e.g., typically less than 8 weeks in a mouse) prior to undergoing full differentiation. HSCs can differentiate into hematopoietic progenitor cells (“HPCs”) that can further differentiate into clonogenic cells, or cells of a single lineage. For example, the differentiation of common lymphoid progenitors (“CLPs”) can produce T lymphocytes (“T cells”), B lymphocytes (“B cells”), and natural killer cells (“NKs”). The differentiation of common myeloid progenitors (“CMPs”) can generate blood cells of other lineages, including erythrocytes, macrophages, granulocytes, and platelets. The maintenance of mature blood-borne cells in the peripheral circulation is critical for various processes, including oxygen delivery and immunological protection.
Maintaining a stable supply of mature blood cells is essential for nutrient supply, pathogen defense and tumor surveillance in hematopoiesis. However, this homeostasis can be perturbed by a DNA-damaging agent such as ionizing radiation or chemotherapy. Ionizing radiation is a high-frequency radiation that has very high energy and the capacity to remove an electron from an atom. When ionizing radiation passes through a cell, its high energy causes intracellular atoms and molecules to become excited, or “ionized”. This ionization can break chemical bonds, produce free radicals, and damage molecules (e.g. DNA, RNA, proteins, and lipids), which are vital in biological processes.
The blood forming-organs, reproductive organs, digestive organs, skin, bone and teeth are primary targets of radiation. Among the tissues mentioned above, the blood system is most sensitive to radiation due to its high turnover rate. In mouse model, after exposure to irradiation, blood cell numbers drops precipitously (drop stage), reaching a nadir around day 3 (nadir stage). Subsequently, the number of blood cells begins to recover and reaches to a nearly normal level around 30 days post irradiation (recovery stage).
The most critical period for a subject's survival after radiation injury is within the first two weeks. For example, if mice are exposed to 6-7Gy total body irradiation, about the 5th or 6th day following exposure a few of the mice may begin to appear lethargic and start to die. Daily mortality increases to a peak between the 10th and 14th day then gradually subsides. After the 20th day deaths are infrequent and the surviving mice show evidence of recovery.
After exposure to ionizing radiation, radiation-induced DNA damage immediately halts cell cycle progression (cell cycle arrest). During the period of cell cycle arrest, DNA repair machinery is triggered and begins to repair the damage. If the repair is unsuccessful, the cells are removed by a programmed cell death mechanism (apoptosis). HSC apoptosis increases after radiation exposure. At the 7th day post 6.5Gy total body irradiation, which is the time-point when the apoptotic rate reaches the peak, around 20% HSCs (Lin-Sca-1+c-Kit+cells) undergo apoptosis.
In some cells, the cell cycle arrest becomes permanent. These cells lose their proliferation capacity and become senescent. A study on human HSCs (CD133+ cells) demonstrated that, even though these cells were successfully repaired, their ability to self-renew was permanently damaged. An increase in p16Ink4a expression on HSCs also implies the induction of premature senescence in these cells.
In some circumstances, apoptosis and senescence do not functionally remove all of the damaged cells. A small number of cells survive radiation stress with chromosome aberrations. These cells are dangerous due to their genomic instability, and have potential to result in tumorigenesis in the future.
Therefore, ionizing radiation induced-apoptosis is necessary to balance tumorigenesis prevention and organismal survival. Low levels of apoptotic activity are beneficial to tissue regeneration and may promote the restoration of hematopoiesis when cells are exposed to ionizing radiation.